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Differentiation and function of intratumoral memory-phenotype CD8+ T cells

瘤内记忆表型 CD8 T 细胞的分化和功能

基本信息

批准号：
10621183
负责人：
Peter Aidan Savage
金额：
$ 40.5万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-17 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10621183
关键词：
Adult Antigens Area Atypical lymphocyte Autoantigens Automobile Driving Biological Assay Biology CD8-Positive T-Lymphocytes CD8B1 gene Cancer Model Cancer Patient Cell Differentiation process Cells Cues Data Dendritic Cells Development Exhibits FOXP3 gene Gene Expression Profiling Goals Human Immune response Immunologics Individual Infiltration Inflammatory Interferon Type II Knowledge Laboratories Ligands Malignant Neoplasms Malignant neoplasm of prostate Marker Discovery Memory Minor Molecular Mus Mutate Nature Oncogenes Peptides Phase Phenotype Play Population Process Production Proliferating Property Prostatic Neoplasms Recurrence Regulatory T-Lymphocyte Reproducibility Research Role Signal Transduction Specificity T cell infiltration T memory cell T-Lymphocyte T-Lymphocyte Subsets T-cell receptor repertoire Testing Thymus Gland Transplantation Tumor Antigens Tumor Immunity Tumor stage Tumor-Infiltrating Lymphocytes Up-Regulation Work anti-PD-1 cancer cell cancer immunotherapy cancer infiltrating T cells cancer type comparative experience experimental study human disease immune cell infiltrate immune checkpoint blockade insight interest melanoma mouse model novel novel marker pathogen programmed cell death protein 1 receptor response success thymocyte transcription factor transgenic adenocarcinoma of mouse prostate tumor

项目摘要

ABSTRACT While considerable evidence demonstrates that CD8+ TILs reactive to mutated or non-mutated tumor antigens play an important role in anti-tumor immunity, expanding evidence indicates that bona fide tumor-reactive T cells comprise only a minor fraction of all TILs in many human tumors, indicating that most CD8+ TILs have undefined specificity. Based on this long-standing question, we examined the hypothesis that a substantial fraction of TILs may represent CD8+ "memory-phenotype" T cells (CD8-MP cells), a unique population of cells of unknown antigen specificity that comprise 5-10% of CD8+ T cells in unprimed mice, exhibit common hallmarks of prior antigen experience, and have the capacity to rapidly expand and produce IFN-γ during an immune response. In preliminary work, we found that CD8-MP cells make substantial contributions to the immune infiltrate of oncogene-driven prostate tumors, and express high densities of the PD-1 inhibitory receptor. Given these unique insights, we embarked on parallel studies aimed at further elucidating the fundamental biology of CD8-MP cells, using a clonal approach to define the developmental trajectories of these cells. Our new data reveal that the differentiation of many CD8-MP clones is triggered by recognition of self-ligands in the thymus via a reproducible, orchestrated process, challenging current thought suggesting that CD8-MP cells differentiate in the periphery in response to homeostatic signals. In Aim 1, we will define the function of CD8-MP cells in anti-tumor immunity, testing the hypothesis that self-ligand recognition drives the early entry of CD8-MP cells into developing tumors, and that CD8-MP cells enhance anti-tumor immunity by catalyzing broader immune cell infiltration. In addition, we will identify novel markers that can be used to identify intratumoral CD8-MP cells, thereby enabling the broader study of CD8-MP cells in murine cancer models and human cancer patients. In Aim 2, we will elucidate the molecular and cellular mechanisms that direct CD8-MP differentiation, testing the hypothesis that CD8-MP differentiation is a two-step process triggered by TCR-dependent recognition of self-ligands presented by classical dendritic cells in the thymus. We will also utilize a unique T cell antigen discovery assay to identify natural self-peptides recognized by CD8-MP cells, thereby opening new areas of inquiry that were previously inaccessible. Ultimately, defining the function of intratumoral CD8-MP cells and the blueprints of CD8-MP differentiation in mice is expected to open new avenues for the study and manipulation of these cells in humans.

摘要